Luigi Bubacco

Our research aims at investigating the cellular and molecular mechanisms of neurodegeneration, with a particular focus on Parkinson’s disease (PD). A full understanding of PD etiopathogenesis and the causes of the preferential vulnerability of nigrostriatal dopaminergic neurons is still an unsolved puzzle. Among the various determinants of the degeneration of the Substantia Nigra pars compacta, pivotal roles have been addressed to dopamine dyshomeostasis and the accumulation of misfolded proteins in neurons.

We are particularly interested in unraveling the mechanisms that trigger the pathological aggregation of the pre-synaptic protein alpha-synuclein (aSyn) and the impact on neuronal physiology. In this frame, we study the interplay between aSyn aggregation and the disequilibrium of dopamine and its metabolites, combining biochemical and imaging approaches in both in vitro and in vivo models. More recently, we started to explore the physio-pathological role of dopamine as a modulator of glial cell functions and the consequences of dopamine depletion in PD pathology.

Currently ongoing projects focus on:

- investigating the impact of the pathological buildup of the aldehydic dopamine metabolite DOPAL on neuronal homeostasis and functionality, with focus on DOPAL-induced aSyn oligomerization;

- detecting aSyn species in biological fluids of idiopathic and familial PD patients as biomarker for PD, by taking advantage of state-of-art techniques like RT-QuIC;

- elucidating the physio-pathological role of dopamine signaling in microglia and striatal astrocytes and their contribution to PD-associated neuroinflammation.

Pike AF, Szabò I, Veerhuis R, Bubacco L. The potential convergence of NLRP3 inflammasome, potassium and dopamine mechanisms in Parkinson’s disease. NPJ Parkinsons Dis. 2022 Mar 24;8(1):32. doi: 10.1038/s41531-022-00293-z.

Pike AF, Longhena F, Faustini G, Van Eik JM, Gombert I, Herrebout MACFayed MMHE, Sandre M, Varanita T, Teunissen CE, Hoozemans JJM, Bellucci A, Veerhuis R, Bubacco L. Dopmaine signaling modulates microglia NLRP3 inflammasome activation: implications for Parkinson’s disease. J Neuroinflammation. 2022 Feb 16;19(1):50. doi: 10.1186/s12974-022-02410-4.

Masato A, Sandre M, Antonini A, Bubacco L. Patients Stratification Strategies to Optimize the Effectiveness of Scavenging Biogenic Aldehydes: Towards a Neuroprotective Approach for Parkinson's Disease. Curr Neuropharmacol. 2021;19(10):1618-1639. doi: 10.2174/1570159X19666210203162617.

Pike AF, Varanita T, Herrebout MAC, Plug BC, Kole J, Musters RJP, Teunissen CE, Hoozemans JJM, Bubacco L, Veerhuis R. α-Synuclein evokes NLRP3 inflammasome-mediated IL-1β secretion from primary human microglia. Glia. 2021 Jun;69(6):1413-1428. doi: 10.1002/glia.23970.

Masato A, Plotegher N, Thor A, Adams S, Sandre M, Cogo S, De Lazzari F, Fontana CM, Martinez PA, Strong R, Bellucci A, Bisaglia M, Greggio E, Dalla Valle L, Boassa D, Bubacco L. DOPAL initiates αSynuclein-mediated impaired proteostasis in neuronal projections leading to enhanced vulnerability in Parkinson’s disease. bioRxiv pre-print. 2021. doi: 10.1101/2021.06.15.448476.

Masato A, Plotegher N, Boassa D, Bubacco L. Impaired dopamine metabolism in Parkinson's disease pathogenesis. Mol Neurodegener. 2019 Aug 20;14(1):35. doi: 10.1186/s13024-019-0332-6.

Biosa A, Arduini I, Soriano ME, Giorgio V, Bernardi P, Bisaglia M, Bubacco L. Dopamine Oxidation Products as Mitochondrial Endotoxins, a Potential Molecular Mechanism for Preferential Neurodegeneration in Parkinson's Disease. ACS Chem Neurosci. 2018 Nov 21;9(11):2849-2858. doi: 10.1021/acschemneuro.8b00276.

Plotegher N, Berti G, Ferrari E, Tessari I, Zanetti M, Lunelli L, Greggio E, Bisaglia M, Veronesi M, Girotto S, Dalla Serra M, Perego C, Casella L, Bubacco L. DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function. Sci Rep. 2017 Jan 13;7:40699. doi: 10.1038/srep40699.

Plotegher N, Stringari C, Jahid S, Veronesi M, Girotto S, Gratton E, Bubacco L. NADH fluorescence lifetime is an endogenous reporter of α-synuclein aggregation in live cells. FASEB J. 2015 Jun;29(6):2484-94. doi: 10.1096/fj.14-260281.

Plotegher N, Kumar D, Tessari I, Brucale M, Munari F, Tosatto L, Belluzzi E, Greggio E, Bisaglia M, Capaldi S, Aioanei D, Mammi S, Monaco HL, Samo B, Bubacco L. The chaperone-like protein 14-3-3η interacts with human α-synuclein aggregation intermediates rerouting the amyloidogenic pathway and reducing α-synuclein cellular toxicity. Hum Mol Genet. 2014 Nov 1;23(21):5615-29. doi: 10.1093/hmg/ddu275.

Università degli Studi di Padova

MIUR

Fondazione Cassa di Risparmio di Padova e Rovigo

The Michael J. Fox Foundation